tbuckley/cabot-search huggingface dataset:
A Therapeutically Actionable Protumoral Axis of Cytokines Involving IL-8, TNFα, and IL-1β
Authors: Irene Olivera, Rebeca Sanz-Pamplona, Elixabet Bolaños, Inmaculada Rodriguez, Iñaki Etxeberria, Assunta Cirella, Josune Egea, Saray Garasa, Itziar Migueliz, Iñaki Eguren-Santamaria, Miguel F. Sanmamed, Javier Glez-Vaz, Arantza Azpilikueta, Maite Alvarez, María C. Ochoa, Beatrice Malacrida, David Propper, Carlos E. de Andrea, Pedro Berraondo, Frances R. Balkwill, Álvaro Teijeira, Ignacio Melero
Journal: Cancer Discovery (2022)

Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL8 mRNA levels correlate with IL1B and TNF transcripts. Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon carcinoma organoids, and fresh human tumor explants. Although IL8 is absent from the mouse genome, a similar murine axis in which TNFα and IL-1β upregulate CXCL1 and CXCL2 in tumor cells was revealed. Furthermore, intratumoral injection of TNFα and IL-1β induced IL-8 release from human malignant cells xenografted in immunodeficient mice. In all these cases, the clinically used TNFα blockers infliximab and etanercept or the IL-1β inhibitor anakinra was able to interfere with this pathogenic cytokine loop. Finally, in paired plasma samples of patients with cancer undergoing TNFα blockade with infliximab in a clinical trial, reductions of circulating IL-8 were substantiated. IL-8 attracts immunosuppressive protumor myeloid cells to the tumor microenvironment, and IL-8 levels correlate with poor response to checkpoint inhibitors. TNFα and IL-1β are identified as major inducers of IL-8 expression on malignant cells across cancer types and models in a manner that is druggable with clinically available neutralizing agents. This article is highlighted in the In This Issue feature, p. 2007.
How to make the most out of your dermatology placement
Authors: Anisha Bandyopadhyay, Khawar Hussain
Journal: BMJ (2022)

Dermatology is the study of skin, hair, and nails—the skin being the largest organ of the human body. With more than 2000 conditions included in the specialty of dermatology, unsurprisingly dermatological diseases are the most common presentations in general practice.1 Dermatology overlaps with most medical and surgical specialties because skin, hair, and nails can provide helpful clues to diagnoses in paediatrics, ophthalmology, plastic surgery, and ear, nose, and throat, as well as in psychiatry, given the massive psychological impact skin conditions can have on mental health. Medical students need to be competent in basic dermatological skills regardless of their future specialty. Undergraduate training provides limited exposure to dermatology,2 with the average placement for just one week.3 If you are fortunate to have a dermatology placement during medical school, you should optimise your time and prepare for diverse learning environments such as wards, surgical theatres, and clinics, both generalised and specialised. This article aims to guide students on what to expect and how to prepare for, and make the most out of, a dermatology placement. Time and experience are needed to develop a good knowledge of the breadth and depth of dermatology. An understanding of normal skin physiology is important to appreciate what happens when skin becomes diseased. Before a placement begins, revise the anatomy of the skin and adnexa and familiarise yourself with common conditions (box 1). This will solidify your learning and maximise your ability to participate during clinical discussions with dermatologists. Make sure you are comfortable with how to obtain a dermatological focused history, perform an examination, and communicate the findings (box 2). Box 1 ### Dermatological conditions and categoriesRETURN TO TEXT
Editor's Note: The Oncogene DEK Promotes Leukemic Cell Survival and Is Downregulated by Both Nutlin-3 and Chlorambucil in B-Chronic Lymphocytic Leukemic Cells
Authors: Paola Secchiero, Rebecca Voltan, Maria Grazia di Iasio, Elisabetta Melloni, Mario Tiribelli, Giorgio Zauli
Journal: Clinical Cancer Research (2022)

The editors are publishing this note to inform readers of concerns about this article (1). Figures 5C and 6A contain two sets of similar control blots: p53 Nutlin-3 scr.+ in Fig. 5C and p53 Nutlin-3 24 h in Fig. 6A; and tubulin Nutlin-3 DEK+ in Fig. 5C and tubulin Nutlin-3 48 h in Fig. 6A. In addition, the siRNA tubulin scr. 24-hour and 48-hour bands in Fig. 4A are similar to the Normal B cells DEK Nutlin-3 24-hour and 48-hour bands in Fig. 6A.
Fast challenge tests with gadolinium‐based contrast agents to search for an alternative contrast media in allergic patients
Authors: Francisco Vega, Azahara Lopez‐Raigada, Maria Victoria Múgica, Carlos Blanco
Journal: Allergy (2022)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Measures of Insulin Resistance as a Screening Tool for Dysglycemia in Patients With Coronary Artery Disease: A Report From the EUROASPIRE V Population
Authors: Giulia Ferrannini, Dirk De Bacquer, Iris Erlund, Viveca Gyberg, Kornelia Kotseva, Linda Mellbin, Anna Norhammar, Oliver Schnell, Jaakko Tuomilehto, Terhi Vihervaara, David Wood, Lars Rydén
Journal: Diabetes Care (2022)

The optimal screening strategy for dysglycemia (including type 2 diabetes and impaired glucose tolerance) in patients with coronary artery disease (CAD) is debated. We tested the hypothesis that measures of insulin resistance by HOMA indexes may constitute good screening methods.Insulin, C-peptide, glycated hemoglobin A1c, and an oral glucose tolerance test (OGTT) were centrally assessed in 3,534 patients with CAD without known dysglycemia from the fifth European Survey of Cardiovascular Disease Prevention and Diabetes (EUROASPIRE V). Three different HOMA indexes were calculated: HOMA of insulin resistance (HOMA-IR), HOMA2 based on insulin (HOMA2-ins), and HOMA2 based on C-peptide (HOMA2-Cpep). Dysglycemia was diagnosed based on the 2-h postload glucose value obtained from the OGTT. Information on study participants was obtained by standardized interviews. The optimal thresholds of the three HOMA indexes for dysglycemia diagnosis were obtained by the maximum value of Youden's J statistic on receiver operator characteristic curves. Their correlation with clinical parameters was assessed by Spearman coefficients.Of 3,534 patients with CAD (mean age 63 years; 25% women), 41% had dysglycemia. Mean insulin, C-peptide, and HOMA indexes were significantly higher in patients with versus without newly detected dysglycemia (all P < 0.0001). Sensitivity and specificity of the three HOMA indexes for the diagnosis of dysglycemia were low, but their correlation with BMI and waist circumference was strong.Screening for dysglycemia in patients with CAD by HOMA-IR, HOMA2-ins, and HOMA2-Cpep had insufficient diagnostic performance to detect dysglycemia with reference to the yield of an OGTT, which should still be prioritized despite its practical drawbacks.
A Phase 3, Open-Label Study of Lumacaftor/Ivacaftor in Children 1 to Less Than 2 Years of Age with Cystic Fibrosis Homozygous for <i>F508del-CFTR</i>
Authors: Jonathan H. Rayment, Fadi Asfour, Margaret Rosenfeld, Mark Higgins, Lingyun Liu, Molly Mascia, Hildegarde Paz-Diaz, Simon Tian, Rachel Zahigian, Susanna A. McColley
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Previous phase 3 trials showed that treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ⩾2 years with cystic fibrosis (CF) homozygous for the F508del mutation in CFTR (CF transmembrane conductance regulator) (F/F genotype). Objectives: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype. Methods: This open-label, phase 3 study consisted of two parts (part A [n = 14] and part B [n = 46]) in which two cohorts were enrolled on the basis of age (cohort 1, 18 to <24 mo; cohort 2, 12 to <18 mo). For the 15-day treatment period in part A, the lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from part A were used to determine dose-based weight boundaries for part B (24-wk treatment period). Measurements and Main Results: The primary endpoint of part A was pharmacokinetics, and the primary endpoint for part B was safety and tolerability. Secondary endpoints for part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from part A confirmed the appropriateness of part B dosing. In part B, 44 children (95.7%) had adverse events, which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of CF, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was -29.1 mmol/L (95% confidence interval, -34.8 to -23.4 mmol/L). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation, such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin, were observed. Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype, with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population. Clinical trial registered with www.clinicaltrials.gov (NCT03601637).
Antibody evolution to SARS-CoV-2 after single-dose Ad26.COV2.S vaccine in humans
Authors: Alice Cho, Frauke Muecksch, Zijun Wang, Tarek Ben Tanfous, Justin DaSilva, Raphael Raspe, Brianna Johnson, Eva Bednarski, Victor Ramos, Dennis Schaefer-Babajew, Irina Shimeliovich, Juan P. Dizon, Kai-Hui Yao, Fabian Schmidt, Katrina G. Millard, Martina Turroja, Mila Jankovic, Thiago Y. Oliveira, Anna Gazumyan, Christian Gaebler, Marina Caskey, Theodora Hatziioannou, Paul D. Bieniasz, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2022)

The single-dose Ad.26.COV.2 (Janssen) vaccine elicits lower levels of neutralizing antibodies and shows more limited efficacy in protection against infection than either of the two available mRNA vaccines. In addition, Ad.26.COV.2 has been less effective in protection against severe disease during the Omicron surge. Here, we examined the memory B cell response to single-dose Ad.26.COV.2 vaccination. Compared with mRNA vaccines, Ad.26.COV.2 recipients had significantly lower numbers of RBD-specific memory B cells 1.5 or 6 mo after vaccination. Despite the lower numbers, the overall quality of the memory B cell responses appears to be similar, such that memory antibodies elicited by both vaccine types show comparable neutralizing potency against SARS-CoV-2 Wuhan-Hu-1, Delta, and Omicron BA.1 variants. The data help explain why boosting Ad.26.COV.2 vaccine recipients with mRNA vaccines is effective and why the Ad26.COV2.S vaccine can maintain some protective efficacy against severe disease during the Omicron surge.
Androgen effects cause sex-biased impairment of CD8 <sup>+</sup> T cell antitumor activity
Authors: Alessio Bevilacqua, Ping-Chih Ho
Journal: Science Immunology (2022)

Androgen signaling compromises CD8+ T cell effector functions and contributes to sex-biased outcomes in many forms of cancer (see the related Research Article by Kwon et al.).
Exploration of Race and Ethnicity, Sex, Sport-Related Concussion, Depression History, and Suicide Attempts in US Youth
Authors: Shawn R. Eagle, David Brent, Tracey Covassin, Robert J. Elbin, Jessica Wallace, Justus Ortega, Raymond Pan, Martina Anto-Ocrah, David O. Okonkwo, Michael W. Collins, Anthony P. Kontos
Journal: JAMA Network Open (2022)

Racial, ethnic, and sex disparities for concussion incidence and suicide attempts in youth have been reported, but data on the interaction of these variables in a large national data set are lacking. Understanding how race and ethnicity interact with sex and concussion to influence suicide attempts could yield critical information on the sociocultural impact of brain injury and mental health in US youth.To examine the associations of concussion history, race and ethnicity, and sex with reported suicide attempts among adolescents.This population-based cross-sectional cohort study used data from US Youth Risk Behavior Surveillance System (YRBSS) survey respondents between 2017 and 2019. Data were analyzed from May 2021 to January 2022.Respondents reported sport- or recreation-related concussion (yes or no), depression (yes or no), and suicide attempt (yes or no) over the previous 12 months, along with race and ethnicity (categorized as American Indian or Alaska Native, Asian, Black, Hispanic/Latino, multiracial, Native Hawaiian or other Pacific Islander, and White), and sex (male or female).Two Chi-Square Automatic Interaction Detection (CHAID) decision tree models were built. The first was suicide attempt with depression history (SA-DEP), the second was suicide attempt without depression history (SA-NO DEP). CHAID uses risk factors (eg, number of concussions, race and ethnicity, sex) to divide the study sample into a series of subgroups that are nested within each other. Risk ratios (RRs) and 95% CIs were calculated for each subgroup to provide effect estimates.A total of 28 442 youths aged up to 18 years (mean [SD] age, 14.6 [3.0] years; 14 411 [50.7%] female) responded to the survey. The CHAID decision trees revealed a complex interaction between race, sex, and concussion history for attempting suicide, which differed by depression history (overall accuracy, 84.4%-97.9%). Overall, depression history was the variable most strongly associated with SA (adjusted odds ratio, 11.24; 95% CI, 10.27-12.29). Concussion was the variable most strongly associated with SA-DEP (RR, 1.31; 95% CI, 1.20-1.51; P < .001). Black, Hispanic/Latino, or multiracial race and ethnicity were associated with increased risk for SA-DEP compared with others (RR, 1.59; 95% CI, 1.38-1.84; P < .001). American Indian or Alaska Native, Black, and Hispanic/Latino race and ethnicity were associated with increased risk for SA-NO DEP (RR, 1.89; 95% CI, 1.54-2.32; P < .001) compared with the remaining population.These findings suggest that clinicians should consider race, ethnicity, and sex when evaluating the role of sport- or recreation-related concussion on suicide risk among US youth.
Combinatorial genetics reveals the Dock1-Rac2 axis as a potential target for the treatment of NPM1;Cohesin mutated AML
Authors: Alison E. Meyer, Cary Stelloh, Kirthi Pulakanti, Robert Burns, Joseph B. Fisher, Katelyn E. Heimbruch, Sergey Tarima, Quinlan Furumo, John Brennan, Yongwei Zheng, Aaron D. Viny, George S. Vassiliou, Sridhar Rao
Journal: Leukemia (2022)
Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers
Authors: Elena Azzolini, Riccardo Levi, Riccardo Sarti, Chiara Pozzi, Maximiliano Mollura, Alberto Mantovani, Maria Rescigno
Journal: JAMA (2022)

This study examines the risk of long COVID following mRNA vaccination, compared with no vaccination, in health care workers in Italy who had COVID-19 infection.
A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Antiapoptotic Protein in Kidney Cancer
Authors: Treg Grubb, Smruthi Maganti, John Michael Krill-Burger, Cameron Fraser, Laura Stransky, Tomas Radivoyevitch, Kristopher A. Sarosiek, Francisca Vazquez, William G. Kaelin, Abhishek A. Chakraborty
Journal: Clinical Cancer Research (2022)

Advanced/metastatic forms of clear-cell renal cell carcinomas (ccRCC) have limited therapeutic options. Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute/Novartis combined short hairpin RNA (shRNA) dataset, and cross-validation with the CRISPR/Cas9 DepMap (21Q3) dataset, we sought therapeutically actionable dependencies in kidney lineage cancers.We identified preferential genetic dependencies in kidney cancer cells versus other lineages. BCL2L1, which encodes the BCL-XL antiapoptotic protein, scored as the top actionable dependency. We validated this finding using genetic and pharmacologic tools in a panel of ccRCC cell lines. Select BCL-XL-dependent (versus independent) cell lines were then transcriptionally profiled to identify biomarkers and mechanistic drivers of BCL-XL dependence. Cell-based studies (in vitro and in vivo) and clinical validations were used to address physiologic relevance.Inactivation of BCL-XL, but not BCL-2, led to fitness defects in renal cancer cells, and sensitized them to chemotherapeutics. Transcriptomic profiling identified a "BCL-XL dependency" signature, including an elevated mesenchymal gene signature. A mesenchymal state was both necessary and sufficient to confer increased BCL-XL dependence. The "BCL-XL dependency" signature was observed in approximately 30% of human ccRCCs, which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed antitumor efficacy in vivo.Our studies uncovered an unexpected link between cell state and BCL-XL dependence in ccRCC. Therapeutic agents that specifically target BCL-XL are available. Our work justifies testing the utility of BCL-XL blockade to target, likely, a clinically aggressive subset of human kidney cancers. See related commentary by Wang et al., p. 4600.
Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS–MAPK Pathway Inhibition in Pancreatic Cancer
Authors: Mirunalini Ravichandran, Jingjie Hu, Charles Cai, Nathan P. Ward, Anthony Venida, Callum Foakes, Miljan Kuljanin, Annan Yang, Connor J. Hennessey, Yang Yang, Brandon R. Desousa, Gilles Rademaker, Annelot A.L. Staes, Zeynep Cakir, Isha H. Jain, Andrew J. Aguirre, Joseph D. Mancias, Yin Shen, Gina M. DeNicola, Rushika M. Perera
Journal: Cancer Discovery (2022)

Abstract The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS–MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron–sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS–MAPK inhibition. Significance: Reduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy–lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS–MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007
Long-Term Associations between Disaster-Related Home Loss and Health and Well-Being of Older Survivors: Nine Years after the 2011 Great East Japan Earthquake and Tsunami
Authors: Koichiro Shiba, Hiroyuki Hikichi, Sakurako S. Okuzono, Tyler J. VanderWeele, Mariana Arcaya, Adel Daoud, Richard G. Cowden, Aki Yazawa, David T. Zhu, Jun Aida, Katsunori Kondo, Ichiro Kawachi
Journal: Environmental Health Perspectives (2022)

Background: Little research has examined associations between disaster-related home loss and multiple domains of health and well-being, with extended long-term follow-up and comprehensive adjustment for pre-disaster characteristics of survivors. Objectives: We examined the longitudinal associations between disaster-induced home loss and 34 indicators of health and well-being, assessed ∼9y post-disaster. Methods: We used data from a preexisting cohort study of Japanese older adults in an area directly impacted by the 2011 Japan Earthquake (n=3,350 and n=2,028, depending on the outcomes). The study was initiated in 2010, and disaster-related home loss status was measured in 2013 retrospectively. The 34 outcomes were assessed in 2020 and covered dimensions of physical health, mental health, health behaviors/sleep, social well-being, cognitive social capital, subjective well-being, and prosocial/altruistic behaviors. We estimated the associations between disaster-related home loss and the outcomes, using targeted maximum likelihood estimation and SuperLearner. We adjusted for pre-disaster characteristics from the wave conducted 7 months before the disaster (i.e., 2010), including prior outcome values that were available. Results: After Bonferroni correction for multiple testing, we found that home loss (vs. no home loss) was associated with increased posttraumatic stress symptoms (standardized difference=0.50; 95% CI: 0.35, 0.65), increased daily sleepiness (0.38; 95% CI: 0.21, 0.54), lower trust in the community (−0.36; 95% CI: −0.53, −0.18), lower community attachment (−0.60; 95% CI: −0.75, −0.45), and lower prosociality (−0.39; 95% CI: −0.55, −0.24). We found modest evidence for the associations with increased depressive symptoms, increased hopelessness, more chronic conditions, higher body mass index, lower perceived mutual help in the community, and decreased happiness. There was little evidence for associations with the remaining 23 outcomes. Discussion: Home loss due to a disaster may have long-lasting adverse impacts on the cognitive social capital, mental health, and prosociality of older adult survivors. https://doi.org/10.1289/EHP10903
Integrated gradient tissue-engineered osteochondral scaffolds: Challenges, current efforts and future perspectives
Authors: Xiaolian Niu, Ning Li, Zhipo Du, Xiaoming Li
Journal: Bioactive Materials (2022)

The osteochondral defect repair has been most extensively studied due to the rising demand for new therapies to diseases such as osteoarthritis. Tissue engineering has been proposed as a promising strategy to meet the demand of simultaneous regeneration of both cartilage and subchondral bone by constructing integrated gradient tissue-engineered osteochondral scaffold (IGTEOS). This review brought forward the main challenges of establishing a satisfactory IGTEOS from the perspectives of the complexity of physiology and microenvironment of osteochondral tissue, and the limitations of obtaining the desired and required scaffold. Then, we comprehensively discussed and summarized the current tissue-engineered efforts to resolve the above challenges, including architecture strategies, fabrication techniques and